title: PEG-functionalized microparticles selectively target inflamed mucosa in inflammatory bowel disease.
abstract: BACKGROUND
  The systemic therapy of inflammatory bowel diseases (IBD) by oral administration of anti-inflammatory and immunosuppressive agents is characterized by an increased probability of adverse drug reactions. A successful treatment with a simultaneous reduction in adverse events may be achieved by the administration of micro- and nanosized targeted drug delivery systems, which accumulate selectively in inflamed mucosal areas without systemic absorption. We described in a first in vivo study in IBD patients a significantly enhanced, but minor accumulation of non-functionalized poly(lactic-co-glycolic acid) (PLGA) microparticles in ulcerous lesions very recently.
  
  
  OBJECTIVE
  The aim of this study was therefore the assessment of an increased targeting potential of different non-, chitosan- and polyethylene glycol (PEG)-functionalized PLGA micro- and nanoparticles to inflamed intestinal mucosa compared to healthy mucosa.
  
  
  METHODS
  For the quantification of nano- and microparticles, fluoresceinamine-labeled-PLGA was synthesized by carbodiimide reaction. Fluorescent chitosan-, PEG-, and non-functionalized PLGA micro- and nanoparticles with mean hydrodynamic diameters of 3000 nm and 300 nm were prepared by solvent evaporation technique. The targeting efficiencies in terms of particle translocation and deposition were investigated in Ussing chamber experiments. Healthy and inflamed macrobiopsies were received from routine endoscopic examinations of patients with IBD as well as control patients.
  
  
  RESULTS
  One-hundred and one Ussing chamber experiments of patients with IBD (Crohn's disease: n=7 and ulcerative colitis: n=9) as well as healthy control patients (n=5) were performed. Histomorphological and electrophysiological investigations of inflamed mucosal tissues confirmed a significant alteration of mucosal barrier integrity in IBD patients (TER: healthy: 34.1 Ω cm(2); inflamed: 21.6 Ωc m(2); p=0.034). In summary, nanoparticles showed an increased translocation and deposition compared to microparticles in healthy and in inflamed mucosa. Chitosan-functionalized particles adhered onto the tissue surface and thus showed the lowest particle translocation and deposition in healthy and inflamed tissues. PEG-functionalized nanoparticles showed the highest translocation through healthy (2.31%) and inflamed mucosa (5.27%). Moreover, PEG-functionalized microparticles showed a significantly increased translocation through inflamed mucosa (3.33%) compared to healthy mucosa (0.55%; p=0.045). Notably, the particle deposition of PEG-functionalized microparticles was significantly increased in inflamed mucosa (10.8%) compared to healthy mucosa (4.1%; p=0.041).
  
  
  CONCLUSIONS
  Based on the targeted translocation and deposition to inflamed intestinal mucosa, PEG-functionalized PLGA microparticles were qualified as an innovative drug delivery system. These particles may serve as a selective treatment strategy to inflamed mucosal areas in IBD with the potential to improve therapeutic efficacy and to reduce adverse events.
authors.affiliation: Clinic of Internal Medicine IV, University Hospital Jena, Jena, Germany. Electronic address: Christian.Lautenschlaeger@med.uni-jena.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Lautenschläger
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmidt
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
authors.forename: Dagmar
authors.initials: D
authors.lastname: Fischer
authors.forename: Andreas
authors.initials: A
authors.lastname: Stallmach
mesh_terms: D000284:Administration, Oral; D000328:Adult; D016022:Case-Control Studies; D048271:Chitosan / Q000737:chemistry; D003093:Colitis, Ulcerative / Q000473:pathology*; D003424:Crohn Disease / Q000473:pathology*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008863:Microspheres; D053758:Nanoparticles; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D004337:Drug Carriers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D048271:Chitosan
keywords: Colitis; Inflammatory bowel disease; Microparticles; Nanomedicine; Targeted drug delivery; Ussing chamber